Since its discovery in 1989, the Hepatitis C virus (HCV) has emerged as the major ethiologic agent responsible for most cases of transfusion-associated and sporadic non-A, non-B hepatitis (Heim et al., 1999; Dore et al., 2003). HCV is the causative agent of the majority of chronic disease throughout the world. An estimated 170 million persons are infected with HCV worldwide. The infection is usually persistent, and following an asymptomatic period often lasting years, many patients develop chronic liver disease, including cirrhosis and hepatocellular carcinoma.
The size of the HCV epidemic and the limited efficacy of current therapy, based on the use of interferon-alpha (INF-alpha), have stimulated intense research efforts towards the development of antiviral drugs that are both better tolerated and more effective. The most widely established strategy for developing novel anti-HCV therapeutics aims at the identification of low-molecular-weight inhibitors of essential HCV enzymes.
Current treatment of HCV infection involves combinations of IFN with ribavirin (Moll and Kohlbrenner, 2003). Although capable of apparent cures, IFN-based regimens are not effective against key viral genotypes, are poorly tolerated, and are very expensive. Vaccine development is hampered by lack of in vitro propagation systems for HCV and the high genetic variability of this single-stranded RNA virus. Several important viral targets for HCV drug development have been identified: i) the processing of viral polyprotein by virus-specific proteases; ii) viral RNA replication that uses the NS3 helicase and iii) viral NS5B RNA-dependent RNA polymerase; and viral regulatory elements such as the internal ribosomal entry site (Moll and Kohlbrenner, 2003). Recent advances in understanding the replication cycle of HCV and the determination of the crystal structures of several virally encoded enzymes have improved the prospects for development of novel therapies. Proteases and polymerases have been the focus of most drug discovery programs and compounds targeting both enzymes have now entered clinical development. However, there is no known treatment for chronic viral diseases such as HCV.
The invention now seeks to overcome disadvantages of the prior art.